HER3 (also called ErbB3) (SEQ ID NO: 21) is one of four structurally related receptor tyrosine kinases comprising the ErbB/HER protein family or epidermal growth factor receptor (EGFR) family of receptors. These receptors are made up of an extracellular region that contains approximately 620 amino acids, a single transmembrane spanning region, and a cytoplasmic tyrosine kinase domain. The extracellular region of each family member is made up of four subdomains, L1, S1 (CR1), L2 and S2 (CR2), where “L” signifies a leucine-rich repeat domain and “CR” a cysteine-rich region. Activation of these receptors typically requires ligand-induced receptor dimerization. HER3 is unique among this family in that, while it has a ligand (Neuregulin-1, NRG; Heregulin, HRG; see Table 1) binding domain, it has no intrinsic tyrosine kinase activity due to the presence of certain amino acid changes in the kinase domain. Therefore, it can bind ligand, but as a homodimer, does not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members that have kinase activity (e.g., HER1/HER3; HER2/HER3; HER3/HER4), to form active signaling-competent moieties. Of particular note is the pairing with HER2, since the HER2/HER3 combination appears to have the highest proliferative potential through various intracellular pathways including the PI3K/pAKT pathway. When HER3 forms dimers with HER2, the resulting signaling complex can be disrupted by antibodies, such as pertuzumab, directed to the HER2 component. In addition, the affinity of HER3 for HRG may be increased when coexpressed with HER2. Recently, the interactions of HER3 with other cell surface receptors (including those outside of the HER family, such as c-MET) have emerged as important escape mechanisms for resistance to certain anti-cancer agents. Alternate transcriptional splice variants encoding different isoforms of HER3 have been characterized, though not fully. One isoform lacks the intermembrane region and is secreted outside the cell. This form may act to modulate the activity of the membrane-bound form by sequestering ligand. Heterodimerization of HER3 with other receptors leads to the activation of pathways important in cell growth and survival. Therefore, controlled expression and activation of these pathways is a necessity for normal growth of the organism and any impairment of such can lead to disease.
The four members of the HER protein family are capable of forming homodimers, heterodimers, and higher order oligomers upon activation by a subset of potential growth factor ligands. Table 1 below lists known ligands of the HER family of receptors.
TABLE 1ErbB (HER) receptorLigandEGFREpidermal growth factor (EGF)Transforming growth factor alpha (TGFa)Amphiregulin (AR)EpigenEGFR & HER4Betacellulin (BTC)Heparin-binding growth factor (HB-EGF)Epiregulin (EPR)HER2NoneHER3 & HER4Neuregulin 1/Heregulin (NRG-1; HRG)Neuregulin 2 (NRG-2)HER4Neuregulin 3 (NRG-3)Neuregulin 4 (NRG-4)Tomoregulin
In mice, loss of signaling by any member of the ErbB family results in embryonic lethality with defects in organs including the lungs, skin, heart and brain. On the other hand, excessive ErbB/HER signaling is associated with the development of a wide variety of solid tumor types. ErbB-1 (EGFR/HER1) and ErbB-2 (HER2) are found in many human cancers and their excessive signaling may be critical factors in the development and malignancy of these tumors. For example, EGFR is overexpressed in many cancers including lung and colon. Drugs such as cetuximab, gefitinib, erlotinib are used to inhibit the activity of this receptor in those settings. The HER2 gene is amplified and the protein overexpressed in breast cancer, which is currently treated with herceptin, tamoxifen and lapatinib, amongst others. Escape from sensitivity to these treatments is an increasing problem in cancer, and is a major reason why more novel and effective treatments are required. Amplification of the HER3 gene and/or overexpression of its protein have been reported in numerous cancers. Recently, it has been shown that acquired resistance to, e.g., gefitinib can be linked to hyperactivity of HER3. This is linked to an acquired overexpression of c-MET that phosphorylates HER3, which, in turn, activates the PI3K/Akt pathway—a key cell growth/survival pathway.
The HER3 receptor (SEQ ID NO: 21) has unique properties and occupies a key node in cell signaling pathways mediated by the HER receptor family. It is also increasingly implicated in mechanisms of resistance to common cancer therapeutic agents. Since it lacks a functionally active kinase domain, it is not ‘druggable’ with conventional small molecules. However, as a cell surface receptor that relies on interaction with other cell surface receptors for its activity in various key growth, survival and differentiation pathways, it is an attractive target for biopharmaceutical approaches.
Thus, a need exists for therapeutic antibodies that target HER3 receptors and for methods of treating cancers with such antibodies.